Project Summary Substance use disorders (SUDs) are characterized by cycles of uncontrollable drug consumption, abstinence from drug use, and relapse. Investigations in individuals with SUDs and animal models have identified maladaptive brain pathologies that are a consequence of repeated drug use and abstinence. For example, our lab has demonstrated increased encoding of drug-associated stimuli by the prelimbic cortex (PrL) and nucleus accumbens (NAc) core following 1-month (compared to 1-day) cocaine abstinence and these changes are accompanied by heightened drug seeking. Interestingly, other studies have shown that 1-month cocaine abstinence leads to reduced resting state functional connectivity between regions of the medial prefrontal cortex (mPFC; which includes the PrL) and NAc core in anesthetized rats. Further, animal models have also demonstrated that reduced PrL activity following repeated cocaine taking is causally linked with compulsive drug seeking. Critically, these data parallel findings in individuals with SUDs showing increased PFC activity to cocaine-associated cues, against a background of reduced overall PFC activity and corticolimbic resting state functional connectivity following extended periods of abstinence (e.g. 3-4 months). Collectively, these findings demonstrate that prolonged cocaine abstinence is associated with profound changes in PFC and NAc activity and functional connectivity that likely play important roles in relapse. However, whether these seemingly divergent neuroadaptations interact, and the role of each in persistent cocaine seeking has not yet been directly assessed. Furthermore, an innovative treatment strategy for SUDs would be to restore cocaine-induced deficits in PFC?NAc function using non-invasive brain stimulation (NIBS). Several techniques for NIBS have emerged, including transcranial alternating current stimulation (tACS) which employs a sine-wave electric field that can be used to directly modulate cortical oscillations that may be disrupted following prolonged cocaine abstinence. In collaboration with an expert in NIBS and a co-sponsor on this application, Dr. Flavio Frohlich, the Carelli lab developed a translational rat model of tACS. Our tACS approach is relatively noninvasive and is sufficient to modulate activity in the PFC?NAc pathway. Aim 1 will use in vivo electrophysiology to characterize PrL neuronal activity and its functional connectivity with the NAc core following short (1-day) versus prolonged (1-month) experimenter-imposed cocaine abstinence. This will determine whether abstinence-induced alterations in overall versus cue-evoked activity in the PrL?NAc core pathway are related and examine their respective association with cocaine seeking. Aim 2 will determine if tACS can reduce cocaine seeking and restore cocaine abstinence- related changes in PrL?NAc core activity. These experiments will provide crucial insight into the neurobiological mechanisms underlying relapse to cocaine use and the utility of NIBS, particularly tACS, in treating SUDs.